Infectious (Non)tolerance--frustrated commensalism gone awry?

Abstract

Despite advances in medicine, infectious diseases remain major causes of death and disability worldwide. Acute or chronic infectious agents mediate host tissue damage and cause a spectrum of disease as diverse as overwhelming sepsis and shock within hours to persistent tissue inflammation causing organ failure or even cancer over years. Although pathogen exposure can cause disease via host-derived inflammation, pathogens share recognized elements with harmless human commensals. Mouse models and organisms with simpler flora are revealing the dialogue between multicellular hosts and commensal flora. In some instances the persistent inflammation associated with pathogens can be interpreted within a framework of frustrated commensalism in which the host and pathogen cannot complete the requisite dialogue that establishes homeostasis. In contrast, coevolved commensals interact cooperatively with the host immune system, resulting in immunotolerance. Attempts to more thoroughly understand the molecular nature of the dialogue may uncover novel approaches to the control of inflammation and tissue damage.

Figure 1.

Examples of pattern recognition in ancient symbioses. Cross talk between eukaryotic host cells and bacterial commensals is necessary to establish homeostasis. (A) Rhizobial Nod factors (NFs) are recognized by legume PRRs. (B) Vibrio polysaccharides are recognized by squid PRRs. (C) Xenorhabdus proteins are recognized by an unknown nematode receptor. In each case signaling down-regulates the classical “inflammatory” pathway and induces anatomic changes that form a symbiotic niche.

Figure 2.

Pathogens are unable to engage in host–commensal dialogue. An alternate model of host–microbial interactions. (A) Commensals express MAMPs and additional signals in response to host inflammatory mediators that limit inflammation and promote healthy mucosal coexistence. (B) Like commensals, pathogen MAMPs signal through host PRRs and trigger inflammatory mediators, but pathogens do not have recognizable commensal signals to complete the dialogue, and inflammation escalates. As a result, the pathogen is either killed or, through various virulence factors, is able to persist in the host by protecting itself from antimicrobial toxins or by invading spaces where it is shielded from immune effectors.